VITAMIN D REQUIREMENTS DURING PREGNANCY, LACTATION & EARLY CHILDHOOD: A MOVING TARGET?
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VITAMIN D REQUIREMENTS DURING PREGNANCY, LACTATION & EARLY CHILDHOOD: A MOVING TARGET? Carol L. Wagner, M.D. & Bruce W. Hollis, Ph.D. Medical University of South Carolina Charleston, South Carolina Funded in part by the following: Thrasher Research Fund; NIH R01 HD047511 & 5R01HD043921; MUSC Clinical & Translational Research Center; Division of Neonatology and Children’s Hospital Fund
Disclaimer Mead Johnson sponsors programs such as this to give healthcare professionals access to scientific and educational information provided by experts. The presenter has complete and independent control over the planning and content of the presentation, and is not receiving any compensation from Mead Johnson for this presentation. The presenter’s comments and opinions are not necessarily those of Mead Johnson. In the event that the presentation contains statements about uses of drugs that are not within the drugs' approved indications, Mead Johnson does not promote the use of any drug for indications outside the FDA-approved product label.
VITAMIN D REQUIREMENTS DURING PREGNANCY, LACTATION & EARLY CHILDHOOD: A MOVING TARGET? Carol L. Wagner, M.D. & Bruce W. Hollis, Ph.D. Medical University of South Carolina Charleston, South Carolina Funded in part by the following: Thrasher Research Fund; NIH R01 HD047511 & 5R01HD043921; MUSC Clinical & Translational Research Center; Division of Neonatology and Children’s Hospital Fund
Disclosure Slide I have no conflict of interest to disclose with regard to this presentation.
What we will cover today… Why are we deficient in vitamin D? What is optimal and what is not? Link between vitamin D and other long latency diseases—role of the innate immune system Issues specific to pregnancy, lactation & early infancy
Evidence of the Epidemic
Why is vitamin D deficiency so prevalent?
First, let’s look at what
vitamin D is…under certain circumstances
7-dehydrocholesterol in skin (SPF > 8, clothes, glass) Major Source: Sun
(−)
Previtamin D3
UVB (290-315 nm)
Thermal heat from skin
Vitamin D3 (Cholecalciferol)
Minor Source: Dietary
Vitamin D2 (ergocalciferol):
Plants/supplements
Vitamin D3 (Cholecalciferol):
Fish (cod liver oil), meat, fortified milk, egg
yolk, butter
25-hydroxylase
Parathyroid hormone
(+)
1-hydroxylase
1,25-dihydroxyvitamin D3
25-hydroxyvitamin D3 ↑Calcium absorption (small intestine)
↑Urinary calcium reabsorption (kidney)
25(OH) D3 ↑Bone mineralizationCommittee on Nutrition, Pediatrics, 1963
Interesting Facts
Concern in 1950’s that vitamin D given to
pregnant women was teratogenic
Concern that even for some individuals doses
of vitamin D above 400 IU/day could be toxic
In 1964, no quantitative means of assessing
circulating concentrations of vitamin D
In fact, at that time, unproven that vitamin D was further metabolized
within the body
By 1967, vitamin D was viewed by the medical
community as a significant causative factor in
Supravalvular Aortic Stenosis Syndrome (SAS)
Taussig, H.B. 1966. Possible injury to the cardiovascular
system from vitamin D. Ann Intern Med 65:1195-1200.
Friedman, W.F. 1967. Vitamin D as a cause of the
supravalvular aortic stenosis syndrome. Am Heart J
73:718-720.SAS Syndrome—the Dogma
Premise: Maternal vitamin D supplementation during pregnancy
caused SAS syndrome, the elfin facies and other findings
described
Animal models were developed to show that toxic excesses of
vitamin D during pregnancy would result in SAS
Antia, A.V., Wiltse, H.E., Rowe, R.D., Pitt, E.L., Levin, S.,
Ottesen, O.E., and Cooke, R.E. 1967. Pathogenesis of
the supravalvular aortic stenosis syndrome. J. Pediatr
71:431-441.
Seelig, M. 1969. Vitamin D and cardiovascular, renal and
brain damage in infancy and childhood. Ann NY Acad Sci
147:537-582.
Pharmacologic doses of vitamin D (hundreds of thousands of IU)
were given to animals creating hypervitaminosis D with
hypercalcemia.What we were to find out…
That SAS was not caused by too
much vitamin D per se
But what, in fact, is a genetic disorder
called Williams SyndromeWilliams Syndrome
A severe genetic affliction
related to elastin gene
disruption
Caused by deletion of
elastin and contiguous
genes on chromosome
7g11.23
Characterized by
multiorgan involvement
(including SAS),
dysmorphic facial features,
and a distinctive cognitive
profileMisattribution of vitamin D as the cause of SAS
Williams Syndrome patients often exhibit abnormal
vitamin D metabolism
Exaggerated response of circulating 25(OH)D to
orally administered vitamin D
Susceptible to bouts of idiopathic hypercalcemia
Morris, C.A., and Mervis, C.B. 2000. William's syndrome and related
disorders. Ann Dev Genomics Human Genet 1:461-484.
This relationship was suspected as early as 1976
but was not definitively made until 1991:
Becroft, D.M.O., and Chambers, D. 1976. Supravalvular aortic
stenosis-infantile hypercalcemia syndrome: in vitro hypersensitivitiy to
vitamin D and calcium. J. Med. Genetics 13:223-228.Second Problem:
What constitutes sufficiency?
Even today we do not know full what is sufficiency for
infants, children and adolescents—we are just beginning
to learn
View that vitamin D was needed most for growing
bones, i.e. in children with little requirement beyond
childhood
For adults, the requirement was set at 200 IU vitamin
D/day—which was viewed as a ‘liberal amount’.
National Academy of Sciences. Recommended
dietary allowances. 1989 Washington, D.C.: National
Academy Press.
The premise: all that one needed could be obtained from
one glass of milk or sticking your arm out of the car
window for 10 minutes three times a week.What is the optimal circulating concentration of 25(OH)D in humans? An office worker, covered in sunscreen, inactive, general sun paranoia (2-15 ng/mL) Field worker (40-70 ng/mL) Lifeguard (60-90 ng/mL) A Pregnant woman and her developing fetus??? A lactating woman and her breastfeeding infant??? Children from early childhood through adolescence???
Haddad and Chyu, JCEM 1971, 33: 992-995
Group No. Age Consumption Weekly Plasma
(years) Of D Weekly Exposure to 25 – HCC
(units) Sunlight (ng/ml)
(hours)
Normal Adult
Volunteers 40 30.2 ± 12.9 2230 ± 1041 8.8 ± 6.1 27.3 ± 11.8
Biliary
Cirrhosis 4 1.5 - 55 2500 (est.) __________ 6.4 ± 2.6*
Lifeguards
8 18.5 ± 2.0 2895 ± 677 53.0 ± 10.3 64.4 ± 8.7*
* P < .001 + values represent mean ± SDHaddad and Chyu article This article became the basis for “normal vitamin D status” in humans. It was not powered to do so and was actually describing a method to measure 25(OH)D reliably and more easily in the laboratory.
“Normal” Vitamin D Status Should NEVER have been defined by Gaussian distribution This is similar to defining “normal” estrogen levels by sampling a population of women who are primarily postmenopausal. There is a range that is associated with better health below which there are higher rates of disease states—we know this in 2009—we did not know this even five years ago.
Problem #3— Sunscreen and Lifestyle Changes
Matsuoka, L.Y., Wortsman, J., and Hollis, B.W. 1990. Use of topical sunscreen for the evaluation of regional synthesis of vitamin D3. J Amer Acad Dermatol 22:772-775.
Adequate Intake for Vitamin D
Children: 400 IU/d approximated from one
teaspoon of cod-liver oil
(Park, JAMA 1940:115:370-9)
Even today, this is sound advice when you look at it on a per kilogram
basis.
Adults: One-half (200 IU)/d the infant dose to
ensure that adults obtain some from the diet
(Blumberg et al, Pediatrics 1963;31:512-25)
Considered a “generous allowance” in the 1989 version of
the American recommended dietary allowancesIndoor Air Quality Act of 1989
Average American spends 93% of their time
indoors
Profound implications for endogenous
synthesis of vitamin D3
1989. Report to Congress on Indoor Air Quality,
Volume II: Assessment and Control of Indoor Air
Pollution. Office of Air and Radiation. U.S.
Environmental Protection Agency EPA 400-1-89-
001C, pp. I, 4-14What determines your vitamin D
status?
Degree of skin pigmentation
Sunlight exposure
Dietary contribution (30 associated with decreased circulating
25(OH)D as fat serves as a vitamin D reservoirWhat determines your vitamin D
status if you are a fetus or
neonate?
Neonatal vitamin D status direct reflection of
maternal status
Neonatal levels are ~0.6-0.7 of maternal levels
In Charleston, SC, 100 cord blood samples were
collected at delivery:
Mean gestational age: 37.4 + 3.2 weeks (range 27-41;
median 38).
> 80% of the cohort delivered greater than 37 weeks’
gestation.
25(OH)D mean + SD for the cohort: 13.5 + 8.3
ng/mL.
By race, there were significant differences between
groups (pCord Blood 25(OH)D by Season and Race
Group All Year April 1 – October 31 November 1 – March 31
All 13.5 + 8.3 (n=100) 19.5 + 9.6 (n=15)* 12.3 + 7.7 (n=83)
African
10.5 + 6.0 (n=67)* 13.1 + 4.0 (n=9) 10.1 + 5.7 (n=58)*
American
Caucasian 19.5 + 9.6 (n=33**)* 29.0 + 7.0 (n=6)* 17.7 + 9.2 (n=25)*
*p value< 0.0001; **season missing for 2 cases
Basile L, Taylor S, Quinones L, Wagner C, Hollis B 2007 Neonatal vitamin D status at birth at
latitude 32o72': Evidence of widespread deficiency. J Perinatology 27(9):568-571.Substrate Deprivation Why are maternal and neonatal vitamin D levels so low? The vitamin D endocrine system is the ONLY steroid endocrine system in the body that is almost always limited by substrate availability due to latitude, lifestyle, race etc. Vitamin D conversion to 25(OH)D 25(OH)D conversion to 1,25(OH)2D in extra-renal sites
Vitamin D Status in Primates and Early Humans
Serum 25(OH)D nmol/L
Winter
160
43o N
120
Latitude
A
80 80
Humans
40 exposing
full skin Blood
0
Old-World Primates
surface to Levels Northern People
Taking
Sunshine’s “Normal” when taking
4000 IU/day
UVB 1000 IU/day
Physiological adult intake
Sources, include Cosman, Osteoporosis Int 2000; Fuleihan NEJM 1999; Scharla Osteoporosis Int 1998; Vieth AJCN 1999, 2000Stages of Vitamin D Deficiency in Infants Stage I: Hypocalcemia & euphosphatemia Stage II: Eucalcemia, hypophosphatemia, & slight increase in skeletal alkaline phosphatase Stage III: Hypocalcemia, hypophosphatemia, & increased alkaline phosphatase
Consequences of Vitamin D Insufficiency
Calcium absorption1
When vitamin D status is sufficient, absorption of dietary
calcium is approximately 30% to 40%.
As vitamin D status declines, absorption of dietary calcium
declines to about 10% to 15%.
PTH
Low levels of vitamin D leads to increased release of PTH,2
which increases bone resorption and decreases bone mass.
Bone Mass
Given its effect on calcium absorption, vitamin D insufficiency
is associated with bone loss and an increased fracture risk.
1. Holick MF. Curr Opin Endocrinol Diabetes. 2002;9:87–98; Lips P. Endocr Rev. 2001;22:477–501.
2. Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357(3): 266-281.Vitamin D Deficiency
Rickets
Enlargement of skull, joints of long bones and rib cage,
curvature of spine and thighs, generalized muscle
weakness
Osteomalacia
Immune
Immunomodulatory actions
Potent stimulator of innate immune system acting
through toll-like receptors on monocytes and
macrophages
Cancers – leukemia, prostate & breast cancer, psoriasis,
diabetes mellitusClassic Rickets: Obvious deformities correctable but what about other risks?
14 months old 11 years old
Photos courtesy of Dr. Lyndon Key, MUSCHow toxic is vitamin D? The U.S. Nutrition Guidelines state that the lowest observed adverse effect level (LOAEL) for humans is 2,000 IU vitamin D/day
Finland - Historical Recommended intake of Vitamin D for Infants in Finland 1950s – 1964 4000-5000 IU/d 1964 2000 IU/d 1975 1000 IU/d 1992 400 IU/d *No infantile hypercalcemia reported Follow-up of these children 30+ years later shows lower rates of type I diabetes in those who received at least 2000 IU vitamin D/day as infants
A series of landmark studies—focus on safety and redefining the LOAEL Vieth, R. 1999. Vitamin D supplementation, 25- hydroxy-vitamin D concentrations, and safety. Am J Clin Nutr 69:842-856. Vieth, R., Chan, P.C.R., and MacFarlane, G.D. 2001. Efficacy and safety of vitamin D3 intake exceeding the lowest observed adverse effect level (LOAEL). Amer J Clin Nutr 73:288-294. Heaney RP, et al. Human serum 25- hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 2003; 77:204-210.
Gordon CM et al: Treatment of hypovitaminosis D in infants and toddlers. J Clin Endocrinol Metab 2008 6-wk supplementation with 2000 IU D2/day, 50000 IU D2 weekly or 2000 IU D3/day Three regimen were equivalent in raising 25(OH)D levels with minimal change in serum calcium and equivalent decreases in PTH
Biomarkers for Vitamin D Sufficiency 25(OH)D Intact PTH Bone Mineral Density (BMD) Intestinal Calcium Absorption Mobility responsiveness Insulin sensitivity Beta cell function Immune function ???Presence or absence of long-latency diseases such as diabetes, rheumatoid arthritis, MS, prostate and breast cancers, cardiovascular diseases
Acute and Long Latency Diseases Flu, acute respiratory infections, tuberculosis Various types of cancers, including colon, prostate, and breast cancers Autoimmune diseases such as Lupus, Multiple Sclerosis, Rheumatoid Arthritis, Scleroderma Type 1 Diabetes; Type 2 diabetes, insulin resistance and obesity Osteopenia, osteomalacia and rickets Cardiovascular disease Fetal growth, fetal dentition, and bone mass And the list goes on…
CHRONIC DISEASES
Disease Status of Evidence
osteoporosis ++++
osteoarthritis +
falls/neuromusc. fcn ++++
multiple sclerosis ++
fibromyalgia-like syndrome ++
type I diabetes ++
insulin sensitivity ++
cardiovascular disease +++
pregnancy outcomes ++++
periodontal disease ++++
various cancers ++++
tuberculosis ++++
hypertension ++++
42What do these diverse groups of
disease states all have to do with
vitamin D?Vitamin D and the Innate Immune System In 1903, Niels Ryberg Finsen was awarded the Nobel Prize for his work, demonstrating that UV light was beneficial to patients with Lupus vulgaris. The beneficial effects of UV exposure to tuberculosis patients is also known.
Yet, what went wrong with sanatoriums?
UV
B
UV
B
UV
BCathelicidin (LL-37)
An endogenous antimicrobial peptide
Generated by innate immune system in
response to microbial invasion thru Toll 2
surface receptor on monocytes and
macrophages
Vitamin D Responsive Element (VDRE) also
contained in gene regulatory region of these cell
types•Sera taken from AA subjects Addition
•_______ of __25(OH)D
________
3 restores
with low 25(OH)D inefficient in ability
_______ of __
sera
____
from
____
AA to __
supporting cathelicidin mRNA mediate
_______ induction
_________of__cathelicidin
induction mRNA
____________ _
d. e.
120 Serum 25D3 4 LL37
100
3
F o ld C h a n g e
2 5 D 3 (n M )
80
60 2
40
1
20
0 0
Afr. Amer. Cauc. Afr. Amer. Cauc.Liu P, et al. Toll-like receptor triggering of a vitamin-D
mediated human antimicrobial response. Science
2006; 311
y Support a link between TLRs and
vitamin D–mediated innate immunity
y Suggest differences in ability of
human populations to produce vitamin
D may contribute to susceptibility to
microbial infectionIt also explains these findings— of rickets and infection Rickets is not only associated with skeletal abnormalities but also respiratory infections. In 1994 a brief study demonstrated that respiratory infections in children with elevated alkaline phosphatase levels were eliminated by supplementing them with 60,000 IU vitamin D/wk for a period of 6 wks. Rehman P 1994 Sub-clinical rickets and recurrent infection. J Tropical Pediatr 40:58.
Vitamin D and Pregnancy
Much consternation—Vitamin D deficiency is not limited to children Nesby-O'Dell, S., Scanlon, K., Cogswell, M., Gillespie, C., Hollis, B., Looker, A., Allen, C., Doughertly, C., Gunter, E., and Bowman, B. 2002. Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: Third National Health and Nutrition Examination Survey: 1988-1994. Am J Clin Nutr 76:187- 192.
What was known in 2002…
A subset of pregnant women had or developed
vitamin D deficiency during their pregnancy
Adverse effects known in terms of impaired fetal growth,
dentition, lighter/less dense bones, and rarely, neonatal
seizures from profound hypocalcemia
Supplementation with vitamin D beyond 400 IU/day
was unnecessary and risky—
Remember the teratogenicity data
A scientific review committee at NIH reviewed our
grant to evaluate the vitamin D requirements of the
pregnant woman and thought the study worthy of
doing.
It began a cascade of events that has changed the way we
view vitamin D today.Evidence of the Epidemic: Our Data in South Carolina
Public Health Issue Evident that vitamin D deficiency during pregnancy is a serious public health issue that affects both mother and fetus. Need to establish the vitamin D requirements of the pregnant woman seen as vital in preventing vitamin D deficiency. Objective: Evaluate the safety and effectiveness of high dose vitamin D supplementation in decreasing pregnancy comorbidity risks in a randomized clinical trial
Deficiency during Fetal & Infant Development
Higher risk of maternal preeclampsia
Halhali A, Tovar AR, Torres N, Bourges H, Garabedian M, Larrea F 2000 Preeclampsia is
associated with low circulating levels of insulin-like growth factor 1 and 1,25-
dihydroxyvitamin D in maternal and umbilical cord compartments. J Clin Endocrinol
85(5):1828-2833.
Hypponen E 2005 Vitamin D for the prevention of preeclampsia? A hypothesis. Nutr Rev
63(7):225-32.
Bodnar LM, Catov JM, Simhan HN, Holick MF, Powers RW, Roberts JM 2007 Maternal
Vitamin D Deficiency Increases the Risk of Preeclampsia, vol. 92, pp 3517-3522.
Impaired fetal growth
Brooke OG, Brown IRF, Bone CDM, Carter ND, Cleeve HJW, Maxwell JD, Robinson VP,
Winder SM 1980 Vitamin D supplements in pregnant Asian women: Effects on calcium
status and fetal growth. Brit Med J 1:751-754.
6Brunvand L, Quigstad E, Urdal P, Haug E 1996 Vitamin D deficiency and fetal growth. Early
Human Development 45:27-33.
Impaired dentition
Purvis RJ, Barrie WJ, MacKay GS, Wilkinson EM, Cockburn F, Belton NR 1973 Enamel
hypoplasia of the teeth associated with neonatal tetany: a manifestation of maternal vitamin-
D deficiency. Lancet 2(7833):811-4.
Increased risk of gingivitis and periodontal disease
Dietrich T, Nunn M, Dawson-Hughes B, Bischoff-Ferrari HA 2005 Association between
serum concentrations of 25-hydroxyvitamin D and gingival inflammation. Am J Clin Nutr
82:575-580.
Dietrich T, Joshipura KJ, Dawson-Hughes B, Bischoff-Ferrari HA 2004 Association between
serum concentrations of 25-hydroxyvitamin D3 and periodontal disease in the US population.
Am J Clin Nutr 80(1):108-13.
At this time, not known about other rates of infection or other long-term markersPublic Health Issue Evident that vitamin D deficiency during pregnancy is a serious public health issue that affects both mother and fetus. Need to establish the vitamin D requirements of the pregnant woman seen as vital in preventing vitamin D deficiency Objective: Evaluate the safety of high dose vitamin D supplementation during pregnancy in a randomized control trial starting at 12 weeks of gestation.
Treatment Effects on Circulating 25(OH)D Levels in
Offspring
Neonatal 25(OH)D was significantly correlated with both
treatment group and maternal 25(OH)D levels at
various points during pregnancy:
Significantly different by treatment group at delivery
18.2±10.2 ng/mL (45.5 nmol/L) (control)
22.8±9.8 ng/mL (57.0 nmol/L) (2000 IU)
26.5±10.3 ng/mL (66.3 nmol/L) (4000 IU)
(pThrasher Research Fund Community- Based Study
in Columbia , SC
Diverse group of women randomized to 1 of 2 tx groups at2010 Perspective on Vitamin D
during Pregnancy
Vitamin D supplementation with 4,000 IU vitamin D/day for pregnant
women was safe and effective in achieving vitamin D sufficiency in a
racially diverse group.
To normalize vitamin D metabolism in the pregnant woman, a
circulating 25(OH)D level of at least 40 ng/mL (100 nmol/L) is required.
Higher maternal circulating 25(OH)D was associated with lower risk of
co-morbidities of pregnancy.
Therefore, we recommend for all pregnant women:
Checking 25(OH)D levels at the start of pregnancy
Achieve a 25(OH)D level of at least 40 ng/mL (100 nmol/L) for
optimal conversion of to 1,25(OH)2D
This can be achieved through vitamin D supplementation of 4000
IU/day starting at 12 weeks’ gestationVITAMIN D IN LACTATION
It is widely known that human milk is
deficient in vitamin D.
•Dogma of the 20th CenturyCLINICAL REPORT Prevention of Rickets and Vitamin D Deficiency in Infants, Children, and Adolescents Carol L. Wagner, MD, Frank R. Greer, MD, and the Section on Breastfeeding and Committee on Nutrition Pediatrics 2008;122:1142–1152
Beyond Current
Recommendations
AAP recommends that all breastfed infants
receive vitamin D supplementation starting
within the 1st few days after delivery
Wagner CL, Greer FR, Section on Breastfeeding, Committee on Nutrition. Prevention
of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics
2008:122:1142–1152.
Addresses the infant but not mother’s status:
Could maternal supplementation at higher doses provide
adequate levels in breast milk without toxicity to mother?
This would effectively treat mother and breastfeeding
infant.Will direct maternal vitamin D supplementation meet the requirements of both the mother and her nursing infant?
Cancela, L., LeBoulch, N., and Miravet, L. 1986. Relationship between the vitamin D content of maternal milk and the vitamin D status of nursing women and breastfed infants. J Endocrinol 110:43-50.
Cancela et al. (J Endocrinol 1986;110:43-50.) Circulating 25(OH)D concentrations in breastfed infants are directly related to the vitamin D content of the mothers’ milk
Available evidence indicates that if vitamin D status of the lactating mother is adequate, her breastfeeding infant will maintain a “minimally normal” vitamin D status. Greer FR, Marshall S. Bone mineral content, serum vitamin D metabolite concentrations, and ultraviolet B light exposure in infants fed human milk with and without vitamin D2 supplements. J Pediatr 114 (2) 1989 p:204 -12
Additional Data… Data suggest that doses exceeding 1000 IU vitamin D/d (2,000-10,000 IU/d) required to achieve a robust normal concentration of circulating 25(OH)D Vieth et al. Am J Clin Nutr 2001;73:288-94. Heany et al. Am J Clin Nutr 2003;77:204-10. Hollis & Wagner. Am J Clin Nutr 2004. Hollis & Wagner. J Clin Nutr 2004. Wagner, et al. Breastfeeding Med 2006; 2: 59-70
Two Finnish Studies Maternal supplements with 1000 IU vitamin D/d resulted in a minimal increases in circulating 25(OH)D concentrations in breastfeeding infants Repeated study with 2000 IU vitamin D/d found the vitamin D status of the breastfeeding infants improved significantly Ala-Houhala M. J Pediatr Gastroenterol Nutr 1985;4:220-6. Ala-Houhala et al. Arch Dis Child 1986;61:1159-63.
Important Considerations Regarding Vitamin D
Status
When a woman is deficient in vitamin D, her
developing fetus is deficient.
Similarly, a lactating woman who is deficient in
vitamin D, provides breast milk that is deficient
in vitamin D--
therefore, unless her breastfeeding infant is
supplemented, her breastfeeding infant will be
deficient.Main Concerns of High Dose Vitamin D Supplementation Toxicity to both mother and her breastfeeding infant Or that mother would become toxic but that there would be little transfer to infant Human milk is deficient theory There would be a reduction in bone demineralization in mother due to the direct of vitamin D on PTH, with lower levels of calcium to be transferred to the breastfeeding infant.
Vitamin D Requirements during Lactation: High-Dose Maternal Supplementation as Therapy to Prevent Hypovitaminosis D in Both Mother and Nursing Infant. Hollis & Wagner. Am J Clin Nutrition 2004; 80S: 1752S- 1758S.
Vitamin D Supplementation During Lactation 1. To increase the nutritional vitamin D status of the mother 2. To improve the vitamin D nutriture of the breastfeeding infant
Pilot Study #2: Vitamin D Supplementation
Trial of Lactating Mothers and Their Infants
Mothers were randomized to 1 of 2 treatment
groups:
400 vs. 6,400 IU vitamin D3/day for 6 months
starting at 1 month postpartum
Investigators and study team blinded to
assignment group:
Infants whose mothers were randomized to 400
IU/d received 300 IU vitamin D3/day
vs. Infants whose mothers were in the 6,400
IU/day group received placebo
Wagner, et al. Breastfeeding Med 2006; 2: 59-70Results
There were no adverse events in any mother
or infant related to vitamin D
Compliance with the regimen was higher in the
mothers (>90%) than the corresponding infant
Mothers said that they were more often likely
to forget to give their infant vitamins than take
their own pillsResults of 2nd pilot study Vitamin D supplementation of mother with higher doses improved maternal vitamin D status, and in so doing, increased her milk antirachitic activity, and thus, the transfer of vitamin D to her nursing infant. We showed both efficacy and effectiveness— What we have to show now is safety and effectiveness on a larger scale….
NIH-Sponsored Vitamin D Supplementation
Trial of Lactating Women and Their Infants
Two site study: MUSC and University of Rochester
Began enrollment November 2006 in Charleston and
January 2007 in Rochester
Mothers recruited by 4-6 weeks postpartum (n=567)
Rochester: Lactating Mother/Infant Dyad only (n=189)
Charleston: Lactating Mother/Infant Dyad (n=189) & Non-lactating
Mothers (n=189)
Mother and infant dyad followed for 6 mos
Following vitamin D status, bone mineralization and safety
parameters with visits monthly
Recently ended 2000 IU arm of study as treatment
failed to increase infant levels and a disproportionate
number of infants required open label
supplementation with 400 IU/day compared with 400
and 6000 IU groupsEffectiveness of Oral Vitamin D
Supplementation in Breastfeeding Infants
Design:
As part of larger, ongoing vitamin D supplementation trial of fully
lactating women, infants of mothers assigned to the control group
received 400 IU vitamin D3 in one drop per day dosing starting at
one month of age.
Subjects were enrolled throughout the year.
The change in circulating 25(OH)D levels in those infants was
measured.
As part of our data safety and monitoring process, levels of those
infants randomized to the control group in a blinded fashion were
analyzed to determine effectiveness of the daily one drop/day
vitamin D dosing method.
Infant 25(OH)D levels (mean ± S.D.) were measured by
radioimmunoassay at Visits 1 (~1 month of age; baseline), 4 and
7.
Data were analyzed by Paired Student’s t-test and repeated
measures ANOVA; significance was set at 0.05 a priori.
Wagner CL, et al, 2010 J Int EndocrinResults 54 mothers and their infants were enrolled in the study and randomized to the control group in a blinded fashion; 33 have completed the study through visit 7. The mean ± S.D. 25(OH)D at one month (baseline) for the infants was: 16.0 ± 9.3 ng/mL (range 1.0-40.8; n=33) 24 (72.7%) had baseline levels
Infant Weight, Vitamin D Status and Dosage per Body Weight Variable Visit 1 (n=54) Visit 4 (n=27) Visit 7 (n=22) Infant wt (mean ± S.D.) 4.6 ± 0.44 kg 6.8 ± 0.79 kg 8.0 ± 1.03 kg Total circulating 25(OH)D 16.3 ± 8.9 43.3 ± 13.7 42.2 ± 12.3 [ng/mL) IU Vitamin D/body wt (kg) 87.3 ± 8.3 59.5 ± 7.0 50.8 ± 6.2
** **p
Conclusions
Oral vitamin D3 supplementation as an oil emulsion
(400 IU/drop) was associated with significant and
sustained increases in circulating 25(OH)D from
baseline in fully breastfeeding infants through 7
months of age.
We educated parents how to give the vitamin D before
leaving the clinic.
Caveat: It is essential that you show parents how to
dispense any medication—whether it is
acetaminophen or vitamin D.
If a parent can demonstrate how to give a med, then the
chances of overdosing diminish.For pregnant women
4,000 IU vitamin D/day was found to be safe and
effective in raising maternal circulating 25(OH)D
levels
Higher 25(OH)D was associated with lower risk of
preterm labor/birth and overall infections during
pregnancy
As a clinician, you can check a circulating
25(OH)D level to ascertain that patient’s status
and prescribe accordingly, with the goal to
achieve a total circulating 25(OH)D level of 40
ng/mL, the level where there is adequate
substrate to convert 25(OH)D to 1,25(OH)2DFor Lactating Women
Maternal circulating 25(OH)D levels could be
checked—
if levels >60 ng/mL, there is likely no need for supplementation of
breastfeeding infant as maternal milk will have good levels.
HOWEVER, DON’T ASSUME SUFFICIENCY: you would have to
check both maternal and infant levels to assure sufficiency.
Supplement lactating mother with high dose
vitamin D and treat both mother and infant:
Unproven/experimental at this time
Achieve circulating 25(OH)D levels of at least
30 ng/mL in all your patients, and don’t forget
yourself!
When in doubt, check a level…For the breastfeeding infant
Supplement breastfeeding infant with 400 IU
vitamin D3/day to ensure adequate intake
Either achieved through vitamin D only preparations
or as part of a multivitamin preparation
Instruction on how to dose vitamin D is essential: one drop,
one dropper, one mL: specific to each vitamin preparation
Combination fed infants should receive vitamin D
supplementation as well
Exclusively formula-fed infants do not require
supplementation is they are taking in greater than 1 liter
formula per day
Ongoing research will assess the safety and
effectiveness of maternal supplementation with the
premise that making mother replete in vitamin D will
allow adequate transfer of vitamin D in her milk and thus
adequate levels in her breastfeeding babyTable 4. Suggested Vitamin D Supplementation Regimen for Infants, Children and
Pregnant and Lactating Women
Age Group Recommended Daily Caveats to ponder
Vitamin D Intake
(IU/day)
Neonates 400 IU/day This includes premature neonates and infants.
Infants < 1 400 IU/day up to 10 kg;
year then 25-50 IU/kg
Children 25-50 IU/kg For example, a child weighing 20 kg would be given
1-2 yrs 500-1,000 IU/day. Another child weighing 25 kg would
be given 625-1,250 IU/day. One could give the lower
dose during summer months and the higher dose
during winter months.
Children 25-50 IU/kg up to 30 kg
2-5 years
Children 25 IU/kg up to 50 kg
5-12 years
Children >50 kg 2,000-4,000 IU/day depending on BMI
12-17 years
Pregnant >45 kg 4,000 IU vitamin D/day
woman [This recommendation is based on our two
RCT that were completed in 2009 (C. Wagner,
D. Johnson, et al., 2010; C. Wagner, R. McNeil,
et al., 2010; C. L. Wagner, et al., 2010)]
Lactating 4,000 IU/day with refinement of recommendation once
Woman Lactation RCT vitamin D studies have been completed
and analyzed.
From: Wagner CL, et al. New Insights into Vitamin D during Pregnancy, Lactation and Early
Pregnancy. 2010; Hale PublishersIndication for Measurement
When nutritional deficiency of vitamin D is
suspected
Intestinal malabsorption syndromes
Patients on chronic anti-epileptic drugs
Limited exposure to the sun: the average American in
1989 spent 93% of their time indoors—imagine the
stats in 2009!
This happens even in San Diego, especially for those who
work indoors such as a medical center!
Limited intakes of oral vitamin D supplements
Aged, homebound patients
Darkly pigmented individuals
Thorough use of sunscreenConclusions We are in the midst of a vitamin D deficiency epidemic. There are many reasons why, not the least of which is that we made too many assumptions about vitamin D. It is quite likely that chronic nutritional vitamin D deficiency puts all of us at risk for developing debilitating, long latency chronic diseases such as insulin resistance/diabetes, cardiovascular disease, cancer and autoimmune diseases. Society will need to understand the role that vitamin D plays in health—beyond bones and mandate policy changes at the national level. That mechanism of change begins with you.
The children…they areare our
The children…they our future.
future.Thank you
How do I know if the infants and toddler in my practice have Vitamin D deficiencies? What are the stages of Vitamin D deficiency? the clinical signs? the potential latent disease processes associated with Vitamin D deficiency? What patients might be at risk? Who should I screen, how often, and what kind of screening tests should I do for Vitamin D deficiency? How do I treat patients with Vitamin D deficiencies? Sun exposure and Vitamin D How much sun should infants and toddler get? What do SPF sunscreens do to Vitamin D absorption?
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